Coccidiosis caused by obligate intracellular protozoan parasite of the genus Eimeria is a major constraint for modern poultry production. It is considered as one of the most expensive and common diseases of poultry and costs the world's commercial chicken producers at least US$ 1.5 billion annually. Among various Eimeria species, Eimeria tenella, which causes caecal coccidiosis, is highly pathogenic. To date, control of coccidiosis is largely limited to good husbandry and prophylactic chemotherapy using a range of drugs against which resistance is rapidly acquired. Few if any new drugs are in the pipeline to fill this unmet need.
A similar problem is evolving around a human protozoal parasite, plasmodium falciparum, which is the causative agent of malaria. The current generation of anti-malarial therapy includes primarily artemisinin-based combination therapies (ACTs) (Enserink, SCIENCE 2010). Current ACTs that are reasonably far along in the development pipeline are merely variations on the artemisinin theme. Their efficacy in killing parasites is untested. The three artemisinin derivatives currently used in ACTs are so closely related chemically that parasites resistant to one will probably be resistant to all. One drug, called artemisone, has been through a phase II trial for nonresistant malaria but failed to offer major benefits over existing derivatives.
One compound that has been used in combating coccidia is Monensin. This compound is an antibiotic of the spiroacetal family of polyether ionophores, obtained by fermentation of streptomyces cinnamonensin and albus (FIG. 1A-D). Monensin contains seventeen stereogenic centres, a spiroacetal, three tetrahydrofuran rings and two tetrahydropyran rings. For additional background see Cox F. E. G., Int. J. Parasitol., 1998, 28, 165-179; Yadav A. et al. Vet. Parasitol., 2001, 102, 69-75; and Agtarap A. et al. J. Chem. Am. Soc., 1967, 89 (22), 5737-5739. As most polyether receptors of the same family forming pseudo-macrocyclic complexes with the mono- and divalent cations, this compound acts as an ion exchanger, creating a ionic unbalance between the cell and its surrounding environment, unbalance which is at the origin of cell apoptosis. These remarkable pharmacological properties make it a first-rate pharmaceutical or veterinary antiparasitic, particularly active against Coccidia, plasmodia, Gram-positive organisms, and mycoplasmas.
Monensin has been used, for example, to improve milk and meat production in the cattle industry (e.g. RUMENSIN®, Elanco Products). However, toxicity of Monensin in some mammals, like equines (T. Matsuoka et al., “Review of monensin toxicosis in horses”, J. Equine Veterinary Science, 16, 1996, 8-15) has been observed, indicating Monesin derivatives having improved safety profiles could be useful—In addition, monensin and derivatives thereof could be useful against babesiosis, which is a disease caused by a protozoan parasite carried by a tick. Recently, the US Agricultural Research Service (ARS) began working on new ways of protecting cattle in Texas from babesiosis. Babesiosis caused considerable harm to the US cattle industry until the early 20th century, when the parasites were largely eradicated within the United States. The ticks continue to thrive across the border in Mexico, however, and are now found in increasing numbers in southern Texas, due in part to growing populations of wild hoofed animals, such as deer, along the border. ARS researchers in Kerrville, Tex., are testing several ways of eliminating the ticks and mitigating the impact of babesiosis on the local livestock industry. The researchers have also developed a slow-release injectable formulation of the antiparasitic doramectin. Currently, producers with infested pastures have to round up and dip their cattle every two weeks for nine months to clear the infestation, so new treatment options promise to save them considerable effort and expense. Improved monensin derivatives would could be useful in combatting babesiosis, and would almost certainly be more cost-effective and easier to administer, as compared to the slow-release doramectin formulation. Monensin exerts its effect during the development of first-generation trophozoites into first-generation schizonts within the intestinal epithelial cells. It does not interfere with hosts'development of acquired immunity to the majority of coccidial species. However, the emergence of resistance phenomena has become a major problem and up to now, little or no consideration in terms of the structural modification of the given ionophores was assigned to restore their activity. To date, a few modified analogues of monensin have been synthesized primarily for structure-activity relation (SAR) studies, though little if any efficacy data has been generated.
Recently, EP02070522A1 (Mazier et al.) disclosed monensin derivatives modified at several positions, some of which showed efficacy in mice against P. yoelii. However, only several of the recited possible compounds appear to have been synthesized and/or tested. Further, applicants indicate the medicaments preferably further comprise at least one compound having anti-malarial activity, possibly contra-indicating use of the disclosed monensin derivatives as stand-alone anti-malarial agents. No anti-coccidal activity was contemplated.
Other references disclosing synthesis of monensin derivatives include:
MonensinReference NameReference IDModification(s)/Site(s)Organism(s)Rochdi et al.J. Med. Chem. 1996, 39,C25-C26P. falciparum588-595JeminetFR2605221De(hydroxymethyl)-25 deoxy-Eimeria25 oxo-25 monensinGumila et al.Antimicrobial Agents andMethyl ester, lactoneP. falciparumChemotherapy, Mar. 1996,p. 602-608 Vol. 40, No. 3Gaboyard et al.Agric. Biol. Chem., 54 (5),C25-C26B. cereus1149-1155, 1990
The emergence of organisms resistant to classical anti-coccidiosis agents (“coccistats”) and anti-malarial agents, coupled with the scarcity of novel replacement drugs, urges the development of novel active compounds. Rotation of drugs has not proven completely effective in overcoming the resistance problem, and almost no new anticoccidians are being developed for the avian market. There are clearly long-felt and unmet needs for new coccistats having improved resistance profiles.
It is expressly noted that citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. Any foregoing applications, and all documents cited therein or during their prosecution (“application cited documents”) and all documents cited or referenced in the application cited documents, and all documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention.